Microwave-assisted synthesis of naphthalenemonoimides and N-desymmetrized naphthalenediimides

Article abstract of DOI:10.1021/jo200177s

Naphthalenemonoimides and N-desymmetrized naphthalenediimides were synthesized using a stepwise microwave-assisted protocol. The steric and electronic properties of aliphatic amines determined the outcome of the reactions, while in the amino acid series their ability to solubilize the naphthalene dianhydride starting material was crucial. Molecular modeling was used to rationalize the observed selectivity.

Full text of DOI:10.1021/jo200177s

ARTICLE
pubs.acs.org/joc
Microwave-Assisted Synthesis of Naphthalenemonoimides and
N-Desymmetrized Naphthalenediimides
||
||
Koujiro Tambara,†, Nandhini Ponnuswamy,†, Gunther Hennrich,‡ and G. Dan Panto-s*,†,§
†University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
‡Departamento de Quimica Organica, Universidad Autonoma de Madrid, 28049 Cantoblanco, Spain
§Department of Chemistry, University of Bath, Bath BA2 7AY, United Kingdom
S Supporting Information
b
ABSTRACT: Naphthalenemonoimides and N-desymmetrized naphtha-
lenediimides were synthesized using a stepwise microwave-assisted
protocol. The steric and electronic properties of aliphatic amines
determined the outcome of the reactions, while in the amino acid series
their ability to solubilize the naphthalene dianhydride starting material
was crucial. Molecular modeling was used to rationalize the observed
selectivity.
’ INTRODUCTION
Mild stepwise functionalization of NDA (1) using R-amino
acids and microwave dielectric heating was previously reported
by the Sanders group as an efficient one-pot method for the
synthesis of NDIs. This method is particularly suitable for
symmetrically substituted NDIs and has found limited applica-
tion to N-desymmetrized derivatives.8 The literature regarding
efficient synthesis and isolation of NMIs 2, however, is scant due
to the difficulty involved in controlling the reaction of 1 equiv of
an amine with a cross-conjugated molecule containing two
equivalent electrophilic sites such as NDA.
We report herein the stepwise and high-yielding synthesis of
naphthalenemonoimides (NMIs) and N-desymmetrized naphtha-
lenediimides (NDIs). We also investigate the factors which influ-
ence the efficiency of this microwave-assisted process, such as the
steric crowding at the R-carbon, the solubility of the amine
reactant, and the noncovalent interaction between the reagents.
The main benefits of this method are the straightforward
synthesis and purification of NMIs, the ability to control the
reactivity of naphthalene dianhydride (NDA), and the produc-
tion of N-desymmetrized NDIs with a broad range of structural
variety. Furthermore, the observed selectivity for the monofunc-
tionalization of NDA was rationalized using molecular modeling
at the ab initio level.
The NDIs represent a class of compounds with an electron-
deficient π-system whose electronic and spectroscopic proper-
ties have led to their extensive study in the field of supramolecular
chemistry.1 As an electron-acceptor motif, their ability to form
donorꢀacceptor interactions has been widely exploited in the
construction of molecular devices and machines.2 The electronic
properties of the π-surface, however, may be altered by core
substitution: the π-acidity of unsubstituted NDIs has facilitated
the development of transmembrane anion transport systems,3
while the attachment of electron-donating substituents at the
naphthyl core can be employed in the synthesis of electroopti-
cally active molecular materials.4 Water-soluble NDI derivatives
have been employed by the Iverson group as DNA intercalators,5
while the Sanders group has used them as building blocks in
dynamic combinatorial libraries, leading to the formation of a
wide variety of catenanes.6 Organic-soluble amino acid-functio-
nalized NDI derivatives have been shown to spontaneously self-
assemble into hydrogen-bonded helical nanotubes with a well-
defined interior cavity capable of complexing various guests,
including fullerenes, ion pairs, and polyaromatic hydrocarbons.7
’ RESULTS AND DISCUSSION
All reactions were run in a dedicated microwave reactor in
pressure-resistant, tightly sealed tubes. The reactions were carried
out in two stages, first a mild heating at 40 °C (amino acids and
their derivatives) or 75 °C (alkylamines) for 5 min followed by
heating for 5ꢀ15 min at 140 °C. The microwave maximum
power input was set to 300 W, and the temperature was held at
75 °C by 5ꢀ20 W pulses. In the second step, the temperature was
set to 140 °C and was maintained by pulses of 30ꢀ50 W. The
synthesis of NMIs 2aꢀg using alkylamines is outlined in
Scheme 1 with the reaction conditions and yields reported in
Table 1, entries 1ꢀ7.
The data from this study suggest that the steric bulk at the R-
carbon influences significantly the outcome of the reaction:
amines attached to a secondary carbon gave consistently higher
yields than when connected to a tertiary carbon. Furthermore,
amines with tertiary R-carbons required longer reaction times
(up to 15 min at 140 °C) to force the condensation to completion.
For 1-adamantanamine, where the nucleophile is attached to
1
a quaternary carbon, the H NMR spectrum of the product
Received: February 8, 2011
Published: March 25, 2011
r
2011 American Chemical Society
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Scheme 1. General Protocol for the Microwave Synthesis of
NMIs 2aꢀv and Desymmetric NDIs 3aꢀva
a Reagents and conditions for alkylamines: (a) RNH2, DMF, (i) 75 °C, 5
min, (ii) 140 °C, 5ꢀ15 min; (b) R0NH2, DMF, (i) 75 °C, 5 min, (ii) 140
°C, 5ꢀ15 min. Reagents and conditions for amino acids: (a) RNH2,
Et3N, DMF, (i) 40 °C, 5 min, (ii) 140 °C, 5 min; (b) R0NH2, Et3N,
DMF, (i) 140 °C, 5 min.
Table 1. Condensations of Alkylamines and Amino Acids
with NDA
Figure 1. 1H NMR spectra of the aromatic naphthalene region: (a) R =
adamantanyl; (b) R = CH(COOH)CH2STrt, after 5 min at 40 °C; (c)
R = CH(COOH)CH2STrt, after 5 min at 40 °C and 5 min at 140 °C
(2i); (d) R = CH(COOH)CH2STrt, R0 = CH(CONH2)CH-
(CH3)CH2CH3 (3n).
[NMI] (%)
entry
amino acid
NMI closed open [NDI] (%)yield (%)
1
2
propargylamine
2-ethyl-n-butylamine
2a
2b
2c
2d
2e
100
100
100
100
100
100
100
61
0
0
0
0
78
86
For all the aliphatic and aromatic amines tested, with the exception
of adamantamine, carrying out the reaction at 140 °C only leads
to the formation of a statistical mixture of dianhydride, mono-
imide, and diimide in a 1:2:1 ratio, which highlights the importance
of this stepwise process.
3a (S)-2-aminoheptane
4a (R)-2-aminoheptane
0
0
59
0
0
44
5
6
7
8
9
4-aminomethylpyridine
0
0
89
(S)-3-amino-1,2-propanediol2f
0
0
69
N-alloc-ethylenediamine
H-L-Asn(Trt)-OH
2g
2h
2i
0
0
88
Due to our work with amino acid-derived NDI-based nano-
tubes and catenanes,6 we investigated the synthesis of NMIs using
amino acids and amino acid esters as starting materials (2hꢀv),
according to Scheme 1. Surprisingly, the amino acids, whose R-
carbons are tertiary, gave yields and purities comparable to those
of amines with secondary R-carbons. In contrast to the NMI
synthesis starting from aliphatic amines, this procedure requires
the reaction to be carried out first at 40 °C rather than 75 °C;
temperatures above 40 °C led to the formation of the undesired
disubstituted NDIs. This suggests that the COOR group of the
amino acid derivatives assists in the collapse of the tetrahedral
intermediate formed in the first steps of the imide formation.
The amino acid-derived NMIs were obtained as a mixture of
open and closed forms, and their ratios were determined by 1H
39
19
44
43
51
32
22
8
0
87b
91b
87 b
85 b
81 b
90 b
85 c
73 c
80 c
83 c
79 c
86 c
78 c
73 c
84 c
H-L-Cys(Trt)-OH
81
0
10 H-L-Cys(Trt)-NH2
11 H-L-Gln(Trt)-OH
12 H-L-His(Trt)-OMe
13 H-L-Tyr(OBn)-OMe
14 H-L-Asp(OBn)-OBn
15 H-L-Cys(tBu)-OH
16 H-L-Glu-OtBu
2j
56
0
2k
2l
57
0
49
0
2m
2n
2o
2p
2q
2r
2s
2t
68
0
70
8
76
16
39
43
38
7
57
4
17 H-L-Ile-OMe
54
3
18 H-L-Ile-OtBu
53
9
19 H-L-Phe-OtBu
78
15
13
11
14
1
20 H-L-Tyr-OtBu
76
11
61
20
NMR integration. The H NMR spectrum of the naphthalene
aromatic region is shown in Figure 1c: due to their symmetry,
only two proton signals are observed for both the closed and the
open forms. The closely spaced doublets (8.75 ppm) represent
the closed form of the monoimide, and the further spaced doublets
(8.6 and 8.25 ppm) represent the open form (Figure 1c, VI).
Performing the reaction at only 40 °C but for a longer period of
time (30 min instead of 5 min) proved to be particularly effective
at reducing the proportion of open monoimide (VI). Increasing
the temperature to 140 °C in the second stage of the reaction
(Scheme 1) produces the NMI in only 5 min, while an increase in
the proportion of the open NMI byproduct (VI) is observed. The
percentage of this open form of the monoimide is higher for the
reaction with amino acid derivatives than for the reaction with
amines. We speculate that the addition of triethylamine in the
former reaction promotes, at high temperatures, the formation of
hydroxide ions which attack any unreacted anhydride moieties,
leading to the formation of open byproduct.
21 H-L-Tyr-OH
2u
28
22 H-L-Tyr(OMe)-OH
2v
66
a Heated for 15 min at 140 °C. b Yield calculated on the basis of NDA as
the sum of the closed and open NMIs. c Conversion calculated on the
basis of the NMI and NDI mixture.
after heating at 75 °C showed the monoreacted open-ring
amide/carboxylic acid intermediate to be the major product
(Figure 1a, I).
However, even upon further heating under high microwave
power (140 °C for 2 h with continuous nitrogen cooling and a
microwave power input of 150ꢀ200W), the 1H NMR spectrum
of the mixture indicated the presence of the same intermediate
(I) along with monodecarboxylated products. No significant
quantities of NDIs or other disubstituted derivatives were
observed under the reaction conditions.
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Scheme 2. Normalized Energy Diagram for the Intermediates in the Reaction Pathwaya
a Hyperchem 8.0, ab initio level: geometry optimization using direct SCF calculation, the 6-31G* basis set, and 0.05 kcal/mol convergence criteria. The
red energy levels correspond to experimentally observed intermediates, while the blue ones are for the starting materials and the two products, NMI
and NDI.
This one-pot procedure for the synthesis of amino acid-derived
NMIs proved to be reliable and efficient, allowing the isolation of
monoimide without extensive purification efforts. The synthesis
was successfully scaled up (5 g of 1) without compromising the
yield or purity.
of the NDI was observed. We propose that intermediate I (Figure 1
and Scheme 2) and indeed the NMI are less reactive toward ring-
opening of the second anhydride by another molecule of the
amino acid than the unreacted NDA. The importance of solubility is
best illustrated by the three tyrosine derivatives investigated:
H-L-Tyr-OtBu, H-L-Tyr(OMe)-OH, and H-L-Tyr-OH, which
have similar π-surfaces (Table 1, entries 20ꢀ22). Their solubility
profiles in DMF at room temperature are very different: the first
and second, being an ester and ether, respectively, show excellent
solubility in DMF, whereas the third is only partially soluble. As
expected, the first and second derivatives rapidly solubilized
NDA in DMF and gave better selectivity toward the NMI
(89% and 80%, respectively) compared to tyrosine (39%), as
shown in Table 1 (entries 20ꢀ22). The enhanced solubility of
NDA in DMF due to its interaction with a suitable amino acid
leads to a 1:1 mixture of NDA and the amino acid in solution and
hence promotes the selective formation of the NMI.
Molecular modeling was performed at the ab initio level for
the possible intermediates of the reaction between NDA (1) and
methylamine. The latter compound was used because of its
limited number of conformations, and it allows us to study the
selectivity observed irrespective of the steric hindrance at the R-
carbon or the solubility (Scheme 2). The modeling is in agree-
ment with the experimental findings: the NMI is of intermediate
energy between the NDA and NDI, and therefore, direct high-
temperature heating leads to a mixture of the three compounds.
The selectivity for the NMI lies in the steps involving inter-
mediates I, II, and III: compound II, although slightly higher in
energy than III, is formed via an intramolecular process and is
therefore favored kinetically. The following steps involve quasi-
The NMI syntheses which produced undesired NDI bypro-
ducts (Table 1, entries 14ꢀ22) led us to further explore the
determinants of the observed monoimide/diimide selectivity.
On comparing entries 8ꢀ22 in Table 1, we conclude that a
higher degree of selectivity in favor of the monoimide was
obtained when the amino acid derivatives contained aromatic
side chains. For amino acids containing the trityl group (Table 1,
entries 8ꢀ12), 100% selectivity for the monoimide was observed.
The product mixture contained 70ꢀ90% NMI when amino acids
with benzyl- and tert-butyl-protected side chains were used. The
lowest selectivity was obtained for the amino acids containing all
alkyl side chains. Also the amino acid esters gave higher yields of
the monoimide than the corresponding amino acids. This trend
can be rationalized by the solubility of the amino acid derivative
and its reactivity toward NDA in DMF at room temperature. The
NDA is insoluble in DMF at room temperature, but is rapidly
solubilized by an amino acid derivative containing aromatic side
chains, which is itself soluble in DMF. We speculate that the
dissolution of NDA in DMF is probably due to πꢀπ interactions
between its extended aromatic core and the amino acid aromatic
side chains. This in turn leads to the formation of an open amide/
carboxylic acid intermediate observed through LCꢀMS and 1H
NMR (Figure 1a).
In the cases where sonication and heating were required to
completely dissolve the reagents, a strong preference for the formation
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Table 2. Condensations of Alkylamines and Amino Acids
with NMIs
entry NMI
amine
NDI timea (min) yield (%)
1
2
2a
2a
2b
2b
2a
2b
2a
2b
2b
2b
2b
2i
(S)-2-aminoheptane
3a
15
15
15
15
5
41
44
32
28
69
61
73
62
82
38
33
94
90
87
89
85
87
94
90
91
93
84
(R)-2-aminoheptane 3b
(S)-2-aminoheptane 3c
3
4
(R)-2-aminoheptane 3d
2-ethyl-n-butylamine 3e
5
6
H-L-Cys(Trt)-OH
H-L-Cys(Trt)-OH
H-L-Ile-OH
3f
5
7
3g
3h
3i
5
8
5
9
H-L-Trp-OH
5
10
11
12
13
14
15
16
17
18
19
20
21
22
4-iodoaniline
3j
15
15
5
4-ethynylaniline
2-ethylbutylamine
H-L-Phe(4-Br)-OH
H-L-Ile-NH2
3k
3l
Figure 2. Side and crystal-packing views of 2b. The thermal ellipsoids
are scaled at the 50% probability level. All hydrogen atoms in the crystal-
packing views have been removed for clarity.
2i
3m
3n
3o
3p
3q
3r
3s
3t
5
2i
5
2i
H-L-Cys(Trt)-OMe
H-L-Cys(Trt)-NH2
H-L-Lys(Boc)-OH
H-L-Gly-OMe
5
irreversible reactions leading to NMI and VII, respectively, with
the former compound being thermodynamically favored. Under
both stringent reaction conditions (140 °C) and in the presence
of triethylamine base, the NMI can react further with the hydroxide
ions to produce V, which, in turn, leads to the formation of VI.
This hypothesis is consistent with the observation that, for NMI
synthesis with amino acids where triethylamine base and heating
at 140 °C are employed, byproducts of type VI are observed in
significant proportions.
Structural proof of the NMI 2b came from single-crystal
X-ray diffraction analysis of crystals grown by slow evapora-
tion of an acetone solution. The single molecule and packing
geometry of 2b are shown in Figure 2. The compound adopts a
P21/c space group where the unit cell contains molecules
arranged in parallel fashion. The packing orientation of 2b
suggests CdOꢀπ-type interactions,9 with a nonconjugating
lone pair of the anhydride oxygen oriented directly toward the
π-system of the anhydride moiety of a neighboring molecule.
2i
5
2i
5
2j
5
2h
2n
2n
2n
H-L-Gly-OMe
5
2-ethylbutylamine
H-L-Gly-OMe
5
3u
5
H-L-Phe-OtBu
3v
5
a For entries 1ꢀ12, the reactions were carried out in two stages, first
heating at 75 °C for 5 min followed by heating for the reported duration
at 140 °C.
statistical mixture was rationalized by theoretical calculations of
the energies of the intermediates in the reaction pathway.
’ EXPERIMENTAL SECTION
General Information. All solvents used were of reagent quality
and purchased commercially. All purchased starting materials were used
without further purification. The microwave reactor used for this study
(CEM Discover) was purchased from CEM Corp. NMR spectra were
recorded on 400 MHz instruments and referenced to the solvent. All
spectra were recorded at 298 K. 1H NMR spectral data are reported as
follows: chemical shift in parts per million on the δ scale, integration,
multiplicity, coupling constants (Hz), and assignments. 13C NMR
spectral data are reported as follows: chemical shifts in parts per million
on the δ scale and carbon environments determined from DEPT
spectra. All spectra were referenced to their respective solvent residual
peaks.10
General Procedure A. Synthesis of Naphthalenemonoi-
mide Derivatives of Alkylamines (2aꢀg). 1,4,5,8-Naphthalene-
tetracarboxylic dianhydride and the corresponding amine (1 equiv) were
suspended in dry dimethylformamide (5 mL) in a pressure-tight
microwave tube. The suspension was sonicated until the mixture became
homogeneous. The reaction mixture was heated under microwave
irradiation for 5 min at 75 ( 5 °C and then for 5ꢀ15 min at 140 (
5 °C. The solvent was removed under reduced pressure, and each
reaction was worked up using a suitable method.
The CdO
distance is 3.54 Å.
π distance is 3.06 Å, while the π-stacking
3 3 3
The synthesis of desymmetrised NDIs 3aꢀv is outlined in
Scheme 1. A wider variety of compounds containing amine func-
tionalities were investigated for the second condensation (Table 2).
Triethylamine was required for the reactions with amino acids to
enable the condensation of the amine by deprotonating the
zwitterion. Aromatic amines gave poorer yields compared to
alkylamines due to their decreased nucleophilicity. They also re-
quired longer reaction times (15 min at 140 °C), which is con-
sistent with the hypothesis that the electronic properties of the
attacking amine also have a significant influence on the yield. The
presence of the open form of the NMI (I) did not hinder the
second condensation, as no peaks corresponding to the unre-
1
acted open NMI were observed in the H NMR spectra of the
final N-desymmetrized NDIs (Figure 1d).
In conclusion, a diverse family of naphthalenemonoimides and
N-desymmetrized naphthalenediimides were synthesized and
isolated via straightforward synthesis and purification. The reac-
tions were critically influenced by the chemical nature of the
amine nucleophile, in particular its steric and electronic proper-
ties at the R-carbon, as well as by its solubility and the ability to
form noncovalent interactions with NDA in the reaction condi-
tions. The selectivity observed in favor of the monoimides over a
General Procedure B. Synthesis of Naphthalenemonoi-
mide Derivatives of r-Amino Acids (2hꢀv). 1,4,5,8-Naphthale-
netetracarboxylic dianhydride and the corresponding R-amino acid (1
equiv) were suspended in dry DMF (5 mL) in a pressure-tight
microwave tube. To this suspension was added dry Et3N (1 equiv).
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The suspension was sonicated until the mixture became homogeneous.
The reaction mixture was heated under microwave irradiation for 5 min
at 40 ( 5 °C and then for 5 min at 140 ( 5 °C. The solvent was removed
under reduced pressure to give a brown residue which was then
suspended in acetone. The suspension was added slowly to vigorously
stirred 1 M HCl(aq). The precipitate thus obtained was filtered and washed
with water and dried in vacuo to yield the product as a colored solid.
General Procedure C. Synthesis of Asymmetrical Naphth-
alenediimide Derivatives of Mixed Alkylamines and r-Ami-
no Acids (3aꢀk). The naphthalenemonoimide derivative, synthesized
according to general procedure A, and the corresponding second amine
(1 equiv) were suspended in dry DMF (5 mL). To this suspension was
added dry Et3N (1 equiv). The suspension was sonicated until the
mixture became homogeneous. The reaction mixture was heated under
microwave irradiation for 5 min at 75 ( 5 °C and then 5ꢀ15 min at 140
( 5 °C. The solvent was removed under reduced pressure, and each
reaction mixture was worked up using a suitable method.
General Procedure D. Synthesis of Asymmetrical Naphth-
alenediimide Derivatives of Mixed Alkylamines and r-Ami-
no Acids (3lꢀv). The naphthalenemonoimide derivative, synthesized
according to general procedure A, and the corresponding second amine
or R-amino acid (1 equiv) were suspended in dry DMF (5 mL). To this
suspension was added dry Et3N (1 equiv). The suspension was sonicated
until the mixture became homogeneous. The reaction mixture was
heated under microwave irradiation for 5 min at 140 ( 5 °C. The solvent
was removed under reduced pressure to give a brown residue which was
then suspended in acetone. The suspension was added slowly to
vigorously stirred 1 M HCl(aq). The precipitate thus obtained was
filtered and washed with water and dried in vacuo to yield the product as
a colored solid.
Calcd for 4C21H19NO5 DMF: C, 68.09; H, 5.45; N, 4.56. Found: C,
68.03; H, 5.84; N, 4.17. Mp: 149 °C dec.
3
2d: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (112 μL) of (R)-2-aminoheptane using general pro-
cedure A. Workup: the brown residue was suspended in acetone and the
suspension added slowly to vigorously stirred 1 M HCl(aq). The
precipitate was filtered and washed with water and dried in vacuo to
yield the product as a light brown solid (88 mg, 32%). 1H NMR (400
MHz, d6-DMSO): 0.80 (3H, m), 1.24 (8H, m), 1.52 (3H, d, J = 6.9 Hz),
5.13 (1H, m), 8.68 (2H, d, J = 7.6 Hz), 8.71 (2H, d. J = 7.6 Hz). Anal.
Calcd for 4C21H19NO5 DMF (CH3)2CO: C, 67.87; H, 5.63; N, 4.40.
3
3
Found: C, 68.16; H, 5.86; N, 4.33. Mp: 148 °C dec.
2e: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (75 μL) of 4-(aminomethyl)pyridine using general
procedure A. Workup: the brown residue was suspended in water,
filtered, and washed with copious water. The solid was dried in vacuo to
yield the product as a brown solid (201 mg, 75%). 1H NMR (400 MHz,
d6-DMSO): 5.29 (2H, s), 7.41 (2H, d, J = 5.9 Hz), 8.49 (2H, m), 8.72
(4H, m). 13C NMR (100 MHz, d6-DMSO): 42.8 (CH2), 122.2 (CH),
124.0 (C), 126.4 (C), 127.1 (C), 128.5 (C), 130.7 (CH), 131.8 (CH),
145.7 (C), 149.6 (CH), 159.6 (C), 162.6 (C). Anal. Calcd for
5C20H10N2O5 2DMF 2H2O: C, 64.50; H, 3.47; N, 8.52. Found: C,
3
3
64.35; H, 3.37; N, 8.20. Mp: 279 °C dec.
2f: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (68 mg) of (S)-3-amino-1,2-propanediol using general
procedure A. Workup: the reaction mixture in DMF was added directly
to diethyl ether. The precipitate was filtered and washed with diethyl
ether to yield the product as a light brown solid (129 mg, 51%). 1H NMR
(400 MHz, d6-DMSO): 3.44 (2H, m), 3.94 (1H, m), 4.03 (1H, dd, J1 =
12.9 Hz, J2 = 4.6 Hz), 4.26 (1H, dd, J1 = 12.9 Hz, J2 = 8.6 Hz), 4.61 (1H,
m), 4.85 (1H, d, J = 5.0 Hz), 8.68 (2H, d, J = 7.6 Hz), 8.71 (2H, d, J = 7.6
Hz). 13C NMR (100 MHz, d6-DMSO): 43.9 (CH2), 64.5 (CH), 68.2
(CH2), 123.7 (CH), 126.2 (C), 127.3 (C), 128.5 (C), 130.3 (CH),
Workup and Characterization Data: Naphthalenemonoi-
mides. 2a: The reaction was performed on 0.932 mmol (250 mg) of
1,4,5,8-naphthalenetetracarboxylic dianhydride (NDA) and 0.932 mmol
(60 μL) of propargylamine using general procedure A. Workup: the
brown residue was suspended in acetone and the suspension added
slowly to vigorously stirred 1 M HCl(aq). The precipitate was filtered
and washed with water and dried in vacuo to yield the product as a light
brown solid (223 mg, 78%). 1H NMR (400 MHz, d6-DMSO): 3.21 (1H,
t, J = 2.4 Hz), 4.82 (2H, d, J = 2.4 Hz), 8.69ꢀ8.74 (4H, m). 13C NMR
(100 MHz, d6-DMSO): 26.7 (CH2), 73.4 (C), 73.5 (C), 124.6 (C),
126.3 (C), 126.7 (C), 130.7 (CH), 131.6 (CH), 131.8 (C), 159.4 (C),
131.8 (CH), 159.8 (C), 162.7 (C). Anal. Calcd for 2C17H11NO7 H2O:
3
C, 58.29; H, 3.45; N, 4.10. Found: C, 57.94; H, 3.58; N, 4.21. Mp:
145 °C dec.
2g:The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (135 mg) of N-alloc-ethylenediamine hydrochloride
using general procedure A. Workup: the brown residue was suspended
in acetone and the suspension added slowly to vigorously stirred 1 M
HCl(aq). The precipitate was filtered and washed with water and dried
in vacuo to yield the product as a light brown solid (258 mg, 88%). 1H
NMR (400 MHz, d6-DMSO): 3.37 (2H, q, J = 5.8 Hz), 4.18 (2H, t, J =
5.8 Hz), 4.37 (2H, d, J = 5.2 Hz), 5.08 (1H, dd, J1 = 1.6 Hz, J2 = 10.4 Hz),
5.19 (1H, dd, J1 = 1.6 Hz, J2 = 17.2 Hz), 5.79 (1H, m), 7.30 (1H, t, J = 6.1
Hz), 8.68 (2H, d, J = 7.6 Hz), 8.71 (2H, d, J = 7.6 Hz). 13C NMR (100
MHz, d6-DMSO): 38.0 (CH2), 40.2 (CH2), 64.1 (CH2), 116.6 (CH2),
123.7 (C), 126.1 (C), 127.2 (C), 128.4 (C), 130.3 (CH), 131.8 (CH),
133.7 (CH), 156.2 (C), 159.7 (C), 162.6 (C). Anal. Calcd for
161.7 (C). Anal. Calcd for 3C17H7NO5 H2O: C, 65.60; H, 2.48; N,
3
4.50. Found: C, 65.67; H, 2.56; N, 4.36. Mp: 251 °C dec.
2b: The reaction was performed on 2.237 mmol (600 mg) of NDA
and 2.237 mmol (291 μL) of 2-ethyl-n-butylamine using general pro-
cedure A. Workup: the brown residue was suspended in acetone and the
suspension added slowly to vigorously stirred 1 M HCl(aq). The pre-
cipitate was filtered and washed with water and dried in vacuo to yield
the product as a light brown solid (608 mg, 77%). The experiment was
successfully scaled up to 5 g of NDA (product yield 5.610 g, 86%). 1H
NMR (400 MHz, d6-DMSO): 0.89 (6H, t, J = 7.4 Hz), 1.34 (4H, m),
1.81 (1H, m), 4.02 (2H, d, J = 7.2 Hz), 8.71 (4H, m). 13C NMR (100
MHz, d6-DMSO): 10.5 (CH3), 23.0 (CH2), 30.7 (CH), 43.5 (CH2),
123.7 (C), 126.1 (C), 127.0 (C), 130.5 (C), 131.6 (CH), 131.8 (CH),
5C20H14N2O7 H2O: C, 60.36; H, 3.65; N, 7.04. Found: C, 60.38; H,
3
3.79; N, 7.29. Mp: 233 °C dec.
2h: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (279 mg) of H-L-Asn(Trt)-OH using general proce-
dure A. Yield: 405 mg, 87%. 1H NMR (400 MHz, d6-DMSO):
2.81ꢀ2.87 (1H, dd, J = 6.51 Hz, J = 15.4 Hz), 3.52ꢀ3.57 (1H, dd, J =
7.54 Hz, J = 15.4 Hz), 6.03ꢀ6.08 (1H, dd, J = 6.86 Hz, J = 14.4 Hz),
7.10ꢀ7.13 (15H, m), 8.70ꢀ8.75 (4H, 2d, 7.5 Hz), 8.76ꢀ8.82 (1H, 2s).
13C NMR (100 MHz, d6-DMSO): 170.5, 168.9, 168.4, 162.3, 161.9,
159.7, 144.7, 137.1, 131.8, 131.0, 129.4, 128.4, 127.3, 126.3, 124.3, 123.9,
69.2, 50.2, 49.9, 35.9. HRMS (ESIþ) (m/z): calcd for C37H25N2O8
[M þ H]þ, 625.1611; found, 625.1603. HRMS (ESIþ) (m/z): calcd for
C37H27N2O9 [M þ H]þ, 643.1717; found, 643.1714.
159.7 (C), 162.7 (C). Anal. Calcd for 2C20H17NO5 H2O: C, 66.66; H,
3
5.03; N, 3.89. Found: C, 66.81; H, 4.71; N, 3.65. Mp: 212 °C dec.
2c: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (112 μL) of (S)-2-aminoheptane using general pro-
cedure A. Workup: the brown residue was suspended in acetone and the
suspension added slowly to vigorously stirred 1 M HCl(aq). The
precipitate was filtered and washed with water and dried in vacuo to
yield the product as a light brown solid (162 mg, 59%). 1H NMR (400
MHz, d6-DMSO): 0.80 (3H, m), 1.23 (8H, m), 1.52 (3H, d, J = 6.9 Hz),
5.13 (1H, m), 8.68 (2H, d, J = 7.6 Hz), 8.71 (2H, d, J = 7.6 Hz). Anal.
2i: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (271 mg) of H-L-Cys(Trt)-OH using general procedure
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The Journal of Organic Chemistry
ARTICLE
A. Yield: 416 mg, 91%. The experiment was successfully scaled up to 5 g
of NDA (6.09 g, 90%). 1H NMR (400 MHz, d-CDCl3): 3.20ꢀ3.29 (2H,
m), 5.51ꢀ5.55 (1H, m), 7.13ꢀ7.34 (15H, m), 8.76 (4H, 2d, J = 8 Hz).
13C NMR (100 MHz, d6-DMSO): 169.5, 168.7, 162.7, 162.2, 160.1,
144.5, 132.3, 131.9, 130.0, 129.4, 129.1, 129.0, 128.4, 127.3, 126.4, 126.1,
125.1, 66.9, 66.8 52.8, 36.2, 31.2, 30.6. HRMS (ESIþ) (m/z): calcd for
C36H23NO7SNa [M þ Na]þ, 636.1087; found, 636.1078. HRMS
(ESIþ) (m/z): calcd for C36H25NO8SNa [M þ Na]þ, 654.1199;
found, 654.1207.
2k: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (290 mg) of H-L-Gln(Trt)-OH using general proce-
dure A. Yield: 405 mg, 85%. 1H NMR (400 MHz, d6-DMSO):
2.24ꢀ2.31 (2H, m), 2.41ꢀ2.46 (2H, m), 5.56ꢀ5.60 (1H, m),
7.12ꢀ7.27(15H, m), 8.43ꢀ8.47 (1H, 2s), 8.76 (4H, s). 13C NMR
(100 MHz, d6-DMSO): 171.2, 170.6, 170.5, 168.4, 162.7, 162.3, 159.7,
144.8, 137.1, 131.9, 131.2, 130.8, 129.4, 128.5, 127.4, 126.4, 126.3, 124.3,
124.0, 69.2, 53.3, 52.9, 32.6, 32.4, 24.3, 24.0. HRMS (ESIþ) (m/z):
calcd for C38H27N2O8 [M þ H]þ, 639.1767; found, 639.1755. HRMS
(ESIþ) (m/z): calcd for C38H29N2O9 [M þ H]þ, 657.1873; found,
657.1878.
2p: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (179 mg) of H-L-Glu-OtBu HCl using general
3
1
procedure A. Yield: 314 mg, 80%. Monoimide:diimide = 61:39. H
NMR (400 MHz, d-CDCl3): 1.43ꢀ1.44 (9H, 2s), 2.38ꢀ2.53 (2H, m),
2.63ꢀ2.71 (2H, m), 5.60ꢀ5.64 (1H, m), 8.82 (4H, s). 13C NMR data
(100 MHz, d6-DMSO): 174.1, 167.9, 162.5, 162.4, 159.7, 131.8, 131.0,
128.6, 126.5, 126.3, 126.2, 124.3, 81.3, 53.8, 53.6, 30.8, 30.3, 27.5, 23.5.
HRMS (ESIþ) (m/z): calcd for C23H20NO9 [M þ H]þ, 454.1133;
found, 454.1127. HRMS (ESIþ) (m/z): calcd for C23H21NO10Na [M
þ Na]þ, 494.1063; found, 494.1062. HRMS (ESIþ) (m/z): calcd for
C32H35N2O12 [M þ H]þ, 639.2190; found, 639.2194.
2q: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (135 mg) of H-L-Ile-OMe HCl using general proce-
3
dure A. Yield: 279 mg, 83%. Monoimide:diimide = 57:43. 1H NMR (400
MHz, d-CDCl3): 0.85ꢀ0.87 (3H, m), 0.99ꢀ1.06 (1H, m), 1.29ꢀ1.30
(4H, m), 2.60ꢀ2.66 (1H, m), 3.71ꢀ3.72 (3H, 2s), 5.41ꢀ5.43 (1H, m),
8.85 (4H, s). 13C NMR (100 MHz, d6-DMSO): 169.2, 169.1, 162.5,
162.4, 159.6, 131.9, 131.6, 128.6, 126.5, 126.1, 125.7 124.6, 57.7, 57.6,
52.2, 33.3, 33.2, 30.7, 24.6, 17.7, 10.9. HRMS (ESIþ) (m/z): calcd for
C21H18NO7 [M þ H]þ, 396.1083; found, 396.1095. HRMS (ESIþ)
(m/z): calcd for C21H20NO8 [M þ H]þ, 414.1189; found, 414.1201.
HRMS (ESIþ) (m/z): calcd for C28H31N2O8 [M þ H]þ, 523.2080;
found, 523.2073.
2l: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (334 mg) of H-L-His(Trt)-OMe HCl using general
3
1
procedure A. Yield: 399 mg, 81%. H NMR (400 MHz, d6-DMSO):
3.41ꢀ3.47 (2H, m), 3.69ꢀ3.70 (3H, 2s), 5.97ꢀ6.00 (1H, m),
6.97ꢀ7.07 (7H, m), 7.25ꢀ7.39 (10H, m), 8.82 (4H, 2d, J = 6.4 Hz).
13C NMR (100 MHz, d6-DMSO): 168.5, 168.3, 162.4, 162.2, 140.3,
140.1, 137.6, 136.5, 131.3, 129.4, 129.1, 128.5, 125.9, 125.6, 123.4, 121.5,
77.3, 52.7, 52.5, 34.1, 30.8. HRMS (ESIþ) (m/z): calcd for
C40H28N3O7 [M þ H]þ, 662.1927; found, 662.1923. HRMS (ESIþ)
(m/z): calcd for C40H30N3O8 [M þ H]þ, 680.2027; found, 680.2035.
2m: The reaction was performed on 0.746 mmol (200 mg) of NDA
2r: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (167 mg) of H-L-Ile-OtBu HCl using general proce-
3
dure A. Yield: 296 mg, 79%. Monoimide:diimide = 62:38. 1H NMR (400
MHz, d6-DMSO): 0.91ꢀ0.94 (3H, m), 0.95ꢀ0.99 (1H, m), 1.17ꢀ1.19
(3H, m), 1.29ꢀ1.31 (9H, 2s), 2.43ꢀ2.46 (1H, m), 5.19ꢀ5.22 (1H, m),
8.73ꢀ8.77 (4H, 2d, J = 8 Hz). 13C NMR (100 MHz, d6-DMSO): 167.6,
162.5, 162.3, 159.6, 131.9, 131.4, 126.5, 126.0, 125.8, 125.7, 124.6, 81.1,
58.7, 58.6, 33.3, 27.5, 24.8, 17.9, 10.9. HRMS (ESIþ) (m/z): calcd for
C24H24NO7 [M þ H]þ, 438.1547; found, 438.1558. HRMS (ESIþ)
(m/z): calcd for C24H26NO8 [M þ H]þ, 456.1658; found, 456.1672.
HRMS (ESIþ) (m/z): calcd for C34H43N2O8 [M þ H]þ, 607.3019;
found, 607.3031.
and 0.746 mmol (240 mg) of H-L-Tyr(OBn)-OMe HCl using general
3
1
procedure A. Yield: 359 mg, 90%. H NMR (400 MHz, d6-DMSO):
3.39ꢀ3.46 (1H, m), 3.60ꢀ3.68 (1H, m), 3.72ꢀ3.73 (3H, 2s),
4.94ꢀ4.95 (2H, 2s), 5.97ꢀ6.06 (1H, m), 6.76ꢀ6.78 (1H, d, J = 9.6
Hz), 7.13ꢀ7.17 (2H, m), 7.27ꢀ7.38 (5H, m), 8.76ꢀ8.83 (4H, 2d, J = 8
Hz). 13C NMR (100 MHz, d6-acetone): 170.2, 168.8, 163.4, 162.9,
160.3, 158.5, 138.3, 133.2, 132.1, 131.5, 131.1, 130.5, 130.4, 129.2, 128.5,
128.4, 128.3, 127.6, 125.3, 115.5, 70.2, 55.7, 55.4, 52.8, 52.6, 34.5. HRMS
(ESIþ) (m/z): calcd for C31H22NO8 [M þ H]þ, 536.1345; found,
536.1342. HRMS (ESIþ) (m/z): calcd for C31H24NO9 [M þ H]þ,
554.1451; found, 554.1446.
2s: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (192 mg) of H-L-Phe-OtBu HCl using general procedure
3
A. Yield: 314 mg, 86%. Monoimide:diimide = 93:7. 1H NMR (400 MHz,
d6-DMSO): 1.365 (9H, m), 3.29ꢀ3.34 (1H, m), 3.56ꢀ3.60 (1H, m),
5.86ꢀ5.90 (1H, m), 7.05ꢀ7.19 (5H, m), 8.70 (4H, s). 13C NMR (100
MHz, d6-DMSO): 167.9, 167.7, 161.9, 159.6, 137.7, 131.9, 131.4, 129.1,
128.7, 128.3, 126.5, 125.8, 125.6, 124.7, 81.63, 51.3, 34.3, 27.6. HRMS
(ESIþ) (m/z): calcd for C27H22NO7 [M þ H]þ, 472.1396; found,
472.1410. HRMS (ESIþ) (m/z): calcd for C27H24NO8 [M þ H]þ,
490.1502; found, 490.1514. HRMS (ESIþ) (m/z): calcd for C40H39N2O8
[M þ H]þ, 675.2706; found, 675.2697.
2n: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (261 mg) of H-L-Asp(OBn)-OBn HCl using general
3
procedure A. Yield: 358 mg, 85%. Monoimide:diimide = 92:8. 1H NMR
(400 MHz, d6-DMSO): 3.07ꢀ3.13 (1H, dd, J = 4.8 Hz, J = 16 Hz),
3.40ꢀ3.47 (1H, dd, J = 8.8 Hz, J = 16 Hz), 5.08ꢀ5.17 (4H, m),
6.15ꢀ6.22 (1H, m), 7.21ꢀ7.30 (10H, m), 8.70ꢀ873 (4H, m). 13C
NMR (100 MHz, d6-DMSO): 170.1, 168.5, 162.1, 159.7, 135.8, 135.5,
131.8, 131.2, 128.7, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7,
126.1, 124.7, 66.9, 66.1, 66.0, 49.7, 33.8. HRMS (ESIþ) (m/z): calcd for
C32H22NO9 [M þ H]þ, 564.1295; found, 564.1301. HRMS (ESIþ)
(m/z): calcd for C32H24NO10 [M þ H]þ, 582.1400; found, 582.1413.
2o: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (132 mg) of H-L-Cys(tBu)-OH using general proce-
dure A. Yield: 247 mg, 73%. Monoimide:diimide = 84:16. 1H NMR (400
MHz, d-CDCl3): 1.3 (9H, s), δ3.47ꢀ3.52 (2H, m), 5.94ꢀ5.98 (1H, m),
8.86 (4H, s). 13C NMR (100 MHz, d6-DMSO): 169.9, 169.8, 162.4,
162.2, 162.0, 159.7, 131.9, 131.4, 129.6, 128.7, 128.5, 126.0, 124.7, 123.7,
54.1, 53.7, 53.6, 42.4, 42.3, 30.6, 26.6. HRMS (ESIþ) (m/z): calcd for
C21H18NO7S [M þ H]þ, 428.0804; found, 428.0801. HRMS (ESIþ)
(m/z): calcd for C21H20NO8S [M þ H]þ, 446.0910; found, 446.0924.
HRMS (ESIþ) (m/z): calcd for C28H31N2O8S2 [M þ H]þ, 587.1516;
found, 587.1517.
2t: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (204 mg) of H-L-Tyr-OtBu HCl using general procedure
3
1
A. Yield: 297 mg, 78%. Monoimide:diimide = 89:11. H NMR (400
MHz, d6-acetone): 1.43ꢀ1.44 (9H, 2s), 3.35ꢀ3.41 (1H, m), 3.55ꢀ3.60
(1H, m), 5.89ꢀ5.93 (1H, m), 6.57 (2H, d, J = 9.2 Hz), 7.03 (2H, d, J =
8.4 Hz), 8.81 (4H, 2d, J = 6.4 Hz). 13C NMR (100 MHz, d6-acetone):
168.7, 162.9, 160.2, 156.7, 133.2, 132.0, 131.0, 130.5, 129.9, 129.1, 127.7,
127.5, 125.1, 115.9, 82.2, 56.7, 34.5, 28.2. HRMS (ESIþ) (m/z): calcd
for C27H22NO8 [M þ H]þ, 488.1345; found, 488.1345. HRMS (ESIþ)
(m/z): calcd for C27H24NO9 [M þ H]þ, 506.1451; found, 506.1460.
HRMS (ESIþ) (m/z): calcd for C40H39N2O10 [M þ H]þ, 707.2605;
found, 707.2609.
2u: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (135 mg) of H-L-Tyr-OH using general procedure A.
Yield: 288 mg, 73%. Monoimide:diimide = 39:61. 1H NMR (400 MHz,
d6-DMSO): 3.19ꢀ3.29 (1H, m), 3.44ꢀ3.49 (1H, m), 5.76ꢀ5.85 (1H,
m), 6.44ꢀ6.50 (2H, m), 6.91ꢀ6.95 (2H, d), 8.69(4H, s). 13C NMR
(100 MHz, d6-acetone): 170.3, 162.0, 161.8, 155.6, 131.8, 131.3, 129.8,
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The Journal of Organic Chemistry
ARTICLE
128.6, 127.7, 127.5, 126.0, 125.6, 124.6, 115.0, 54.8, 54.7, 33.3, 33.2. HRMS
(ESIþ) (m/z): calcd for C23H14NO8 [M þ H]þ, 432.0719; found,
432.0723. HRMS (ESIþ) (m/z): calcd for C23H16NO9 [M þ H]þ,
450.0825; found, 450.0825. HRMS (ESIþ) (m/z): calcd for C32H23N2O10
[M þ H]þ, 595.1353; found, 595.1355.
a brown solid (26 mg, 28%). 1H NMR (400 MHz, d6-DMSO): 0.80 (3H,
m), 0.89 (6H, t, J = 7.5 Hz), 1.23 (8H, m), 1.33 (4H, m), 1.51 (3H, d, J =
6.9 Hz), 1.80 (1H, m), 4.00 (2H, d, J = 7.2 Hz), 5.14 (1H, m), 8.65ꢀ8.67
(4H, m). 13C NMR (100 MHz, d6-DMSO): 10.5 (CH3), 13.9 (CH3),
18.0 (CH3), 21.9 (CH2), 23.0 (CH2), 26.0 (CH2), 31.0 (CH2), 32.7
(CH2), 38.7 (CH), 43.3 (CH2), 49.2 (CH), 126.0 (C), 126.1 (C), 126.2
(C), 126.6 (C), 130.5 (CH), 130.6 (CH), 162.97 (C), 163.02 (C). Anal.
2v: The reaction was performed on 0.746 mmol (200 mg) of NDA
and 0.746 mmol (146 mg) of H-L-Tyr(Me)-OH using general procedure
1
Calcd for 2C27H32N2O4 H2O: C, 70.87; H, 7.27; N, 6.12. Found: C,
A. Yield: 300 mg, 84%. Monoimide:diimide = 80:20. H NMR (400
3
70.80; H, 6.91; N, 5.95. Mp: 144 °C.
MHz, d6-acetone): 3.26ꢀ3.29 (1H, m), 3.51ꢀ3.55 (1H, m), 3.58ꢀ3.59
(3H, 2s), 5.79ꢀ5.87 (1H, m), 6.65ꢀ6.68 (2H, m), 7.06ꢀ7.09 (2H, d),
8.66ꢀ8.71 (4H, m). 13C NMR (100 MHz, d6-acetone): 170.3, 161.8,
159.5, 157.7, 131.8, 131.3, 129.9, 125.8, 125.6, 124.5, 113.6, 54.9, 54.8,
33.3. HRMS (ESIþ) (m/z): calcd for C24H16NO8 [M þ H]þ, 446.0876;
found, 446.0888. HRMS (ESIþ) (m/z): calcd for C24H18NO9 [M þ
H]þ, 464.0982; found, 464.0984. HRMS (ESIþ) (m/z): calcd for
C34H26N2O10 [M þ H]þ, 623.1660; found, 623.1674.
3e: The reaction was performed on 0.491 mmol (150 mg) of 2a and
0.491 mmol (64 μL) of 2-ethyl-n-butylamine using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
1
product as a brown solid (131 mg, 69%). H NMR (400 MHz, d6-
DMSO): 0.89 (6H, t, J = 7.3 Hz), 1.34 (4H, m), 1.81 (1H, m), 3.20 (1H,
t, J = 2.4 Hz), 4.01 (2H, d, J = 7.2 Hz), 4.82 (2H, d, J = 2.4 Hz),
8.68ꢀ8.74 (4H, m). 13C NMR (100 MHz, d6-DMSO): 10.5 (CH3),
22.9 (CH2), 29.0 (CH2), 29.5 (CH2), 31.0 (CH2), 32.8 (CH2), 38.8
(CH), 49.3 (CH), 73.5 (CH), 78.8 (C), 125.6 (C), 126.0 (C), 126.2
(C), 126.9 (C), 130.5 (CH), 130.8 (CH), 161.9 (C), 162.9 (C). Anal.
Calcd for 4C27H32N2O4 H2O (CH3)2CO: C, 70.01; H, 5.44; N, 6.88.
Workup and Characterization Data: Naphthalenediimides.
3a: The reaction was performed on 0.328 mmol (100 mg) of 2a and
0.328 mmol (49 μL) of (S)-2-aminoheptane using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
3
3
1
Found: C, 69.74; H, 5.11; N, 6.62. Mp: 235 °C.
product as a brown solid (54 mg, 41%). H NMR (400 MHz, d6-
3f: The reaction was performed on 0.285 mmol (100 mg) of 2b and
0.285 mmol (103 mg) of H-L-Cys(Trt)-OH using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
DMSO): 0.80 (3H, m), 1.23 (8H, m), 1.51 (3H, d, J = 6.9 Hz), 3.20 (1H,
t, J = 2.4 Hz), 4.82 (2H, d, J = 2.4 Hz), 5.14 (1H, m), 8.69 (2H, d, J = 7.6
Hz), 8.71 (2H, d, J = 7.6 Hz). 13C NMR (100 MHz, d6-DMSO): 13.9
(CH3), 17.9 (CH3), 21.9 (CH2), 26.0 (CH2), 29.5 (CH2), 31.0 (CH2),
32.8 (CH2), 49.3 (CH), 73.5 (CH), 78.8 (C), 125.6 (C), 126.0 (C),
126.2 (C), 126.9 (C), 130.5 (CH), 130.8 (CH), 161.9 (C), 162.9 (C).
1
product as a yellow solid (120 mg, 61%). H NMR (400 MHz, d6-
DMSO): 0.89 (6H, t, J = 7.3 Hz), 1.34 (4H, m), 1.81 (1H, m), 3.11 (2H,
dd, J1 = 4.5 Hz, J2 = 13.0 Hz), 4.01 (2H, d, J = 7.2 Hz), 5.55 (1H, dd, J1 =
4.3 Hz, J2 = 10.5 Hz), 7.17ꢀ7.22 (15H, m), 8.68ꢀ8.74 (4H, m). 13C
NMR (100 MHz, d6-DMSO): 10.5 (CH3), 22.9 (CH2), 30.3 (CH2),
38.8 (CH), 43.4 (CH2), 52.1 (CH), 66.5 (C), 125.0 (C), 126.5 (C),
126.8 (CH), 127.1 (C), 128.0 (CH), 128.4 (C), 129.0 (CH), 130.6
(CH), 131.5 (CH), 144.0 (C), 162.0 (C), 163.0 (C), 169.2 (C). Anal.
Anal. Calcd for 2C24H22N2O4 H2O: C, 70.06; H, 5.63; N, 6.81. Found:
C, 70.32; H, 5.65; N, 6.58. Mp: 162 °C.
3
3b: The reaction was performed on 0.328 mmol (100 mg) of 2a and
0.328 mmol (49 μL) of (R)-2-aminoheptane using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
1
product as a brown solid (58 mg, 44%). H NMR (400 MHz, d6-
Calcd for 2C42H36N2O6S H2O: C, 71.47; H, 5.28; N, 3.97. Found: C,
3
DMSO): 0.80 (3H, m), 1.24 (8H, m), 1.51 (3H, d, J = 6.9 Hz), 3.20 (1H,
t, J = 2.2 Hz), 4.82 (2H, d, J = 2.2 Hz), 5.14 (1H, m), 8.69 (2H, d, J = 7.6
Hz), 8.71 (2H, d, J = 7.6 Hz). 13C NMR (100 MHz, d6-DMSO): 13.9
(CH3), 17.9 (CH3), 21.9 (CH2), 26.0 (CH2), 29.5 (CH2), 31.0 (CH2),
32.8 (CH2), 49.3 (CH), 73.5 (CH), 78.9 (C), 125.7 (C), 126.1 (C),
126.3 (C), 127.0 (C), 130.5 (CH), 130.8 (CH), 161.9 (C), 162.9 (C).
71.18; H, 5.09; N, 3.87. Mp: 156 °C.
3g: The reaction was performed on 0.327 mmol (100 mg) of 2a and
0.327 mmol (119 mg) of H-L-Cys(Trt)-OH using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
1
Anal. Calcd for 2C24H22N2O4 H2O: C, 70.06; H, 5.63; N, 6.81. Found:
product as a yellow solid (156 mg, 73%). H NMR (400 MHz, d6-
3
C, 70.37; H, 5.70; N, 6.53. Mp: 162 °C.
DMSO): 3.21 (1H, m), 4.82 (2H, m), 5.55 (1H, dd, J1 = 4.3 Hz, J2 = 10.3
Hz), 7.19ꢀ7.23 (15H, m), 8.73 (2H, d, J = 7.6 Hz), 8.75 (2H, d, J = 7.6
Hz), 13.15 (1H, s). 13C NMR (100 MHz, d6-DMSO): 29.5 (CH2), 30.3
(CH2), 52.3 (CH), 66.5 (C), 73.5 (CH), 78.9 (C), 125.3 (C), 125.8 (C),
126.3 (C), 126.76 (C), 126.82 (CH), 128.0 (CH), 129.0 (CH), 130.8
(CH), 131.5 (CH), 144.0 (C), 161.90 (C), 161.92 (C), 169.2 (C). Anal.
3c: The reaction was performed on 0.213 mmol (75 mg) of 2b and
0.213 mmol (32 μL) of (R)-2-aminoheptane using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the product as
a brown solid (31 mg, 32%). 1H NMR (400 MHz, d6-DMSO): 0.80 (3H,
m), 0.89 (6H, t, J = 7.4 Hz), 1.23 (8H, m), 1.33 (4H, m), 1.51 (3H, d, J =
6.9 Hz), 1.80 (1H, m), 4.01 (2H, d, J = 7.2 Hz), 5.14 (1H, m), 8.65ꢀ8.68
(4H, m). 13C NMR (100 MHz, d6-DMSO): 10.5 (CH3), 13.9 (CH3),
18.0 (CH3), 21.9 (CH2), 23.0 (CH2), 26.0 (CH2), 31.0 (CH2), 32.7
(CH2), 38.8 (CH), 43.3 (CH2), 49.2(CH2), 126.0 (C), 126.1 (C), 126.2
(C), 126.6 (C), 130.5 (CH), 130.6 (CH), 162.97 (C), 163.02 (C). Anal.
Calcd for 3C39H26N2O6S 4H2O: C, 69.42; H, 4.28; N, 4.15. Found: C,
3
69.28; H, 4.03; N, 3.90. Mp: 194 °C.
3h: The reaction was performed on 0.285 mmol (100 mg) of 2b and
0.285 mmol (37 mg) of H-L-Ile-OH using general procedure B. Workup:
the brown residue was suspended in acetone and the suspension added
slowly to vigorously stirred 1 M HCl(aq). The precipitate was filtered
and washed with water and dried in vacuo to yield the product as a yellow
solid (81 mg, 62%). 1H NMR (400 MHz, d6-DMSO): 0.76 (3H, t, J = 7.3
Hz), 0.89 (7H, t, J = 7.3 Hz), 1.21 (3H, d, J = 6.5 Hz), 1.34 (5H, m), 1.80
(1H, m), 4.01 (2H, d, J = 7.2 Hz), 5.22 (1H, d, J = 9.1 Hz), 8.71 (2H, d,
J = 7.6 Hz), 8.74 (2H, d, J = 7.6 Hz), 12.80 (1H, s). 13C NMR (100 MHz,
d6-DMSO): 10.5 (CH3), 10.9 (CH3), 18.0 (CH3), 22.9 (CH2), 24.7
(CH2), 33.1 (CH), 38.8 (CH), 43.4 (CH2), 57.9 (CH), 125.1 (C), 126.2
(C), 126.4 (C), 126.9 (C), 130.7 (CH), 131.4 (CH), 162.6 (C), 162.9
Calcd for 2C27H32N2O4 H2O: C, 70.87; H, 7.27; N, 6.12. Found: C,
3
71.21; H, 7.04; N, 6.30. Mp: 144 °C.
3d: The reaction was performed on 0.213 mmol (75 mg) of 2b and
0.213 mmol (32 μL) of (S)-2-aminoheptane using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filteredandwashedwithwateranddriedinvacuotoyieldtheproductas
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ARTICLE
(C), 170.2 (C). Anal. Calcd for 2C26H28N2O6 H2O: C, 65.95; H, 6.17;
N, 5.92. Found: C, 65.66; H, 5.86; N, 5.72. Mp: 135 °C.
(1H, dd, J = 5.6 Hz, J = 9.2 Hz), 7.14ꢀ7.32 (20H, m), 8.69 (4H, s). 13
C
3
NMR (100 MHz, d6-DMSO): 170.1 (C), 169.2 (C), 162.1 (C), 161.8
(C), 144.0 (C), 137.3 (C), 131.5 (CH), 131.3 (CH), 131.0 (CH), 129.0
(CH), 127.9 (CH), 126.7 (CH), 126.2 (C), 125.7 (C), 125.6 (C), 119.5
(C), 66.5 (C), 54.4 (CH), 52.3 (CH), 33.6 (CH2), 30.2 (CH2). Mp:
196 °C dec. HRMS (ESIþ) (m/z): calcd for C45H31BrN2O8SNa [M þ
Na]þ, 862.6944; found, 862.6957.
3i: The reaction was performed on 0.285 mmol (100 mg) of 2b and
0.285 mmol (58 mg) of H-L-Trp-OH using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
product as a brown-red solid (123 mg, 82%). 1H NMR (400 MHz, d6-
DMSO): 0.88 (6H, t, J = 7.1 Hz), 1.32 (4H, m), 1.79 (1H, m), 4.00 (2H,
d, J = 7.1 Hz), 5.90 (1H, dd, J1 = 5.5 Hz, J2 = 9.4 Hz), 6.82 (1H, t, J = 7.7
Hz), 6.93 (1H, t, J = 7.7 Hz), 7.04 (1H, d, J = 2.2 Hz), 7.19 (1H, d, J = 8.1
Hz), 7.48 (1H, d, J = 8.1 Hz), 8.64 (4H, m), 10.64 (1H, s). 13C NMR
(100 MHz, d6-DMSO): 10.5 (CH3), 22.9 (CH2), 24.0 (CH2), 38.7
(CH), 43.4 (CH2), 54.2 (CH), 110.6 (C), 111.3 (CH), 118.0 (CH),
118.3 (CH), 120.8 (CH), 123.6 (CH), 125.2 (C), 125.9 (C), 126.2 (C),
126.8 (C), 127.1 (C), 130.5 (CH), 131.1 (CH), 135.9 (C), 162.2 (C),
3n: The reaction was performed on 0.163 mmol (100 mg) of 3c and
0.163 mmol (21 mg) of H-L-Ile-NH2 using general procedure B. Yield:
103 mg, 87%. 1H NMR (400 MHz, d-CDCl3): 0.79ꢀ0.81 (3H, t, J = 6.8
Hz), 1.04 (1H, m), 1.18ꢀ1.20 (3H, d, J = 6.8 Hz), 1.22ꢀ1.29 (1H, m),
2.70ꢀ2.78 (1H, m), 3.19ꢀ3.22 (2H, m), 5.31ꢀ5.34 (1H, d, J = 10.4
Hz), 5.52ꢀ5.56 (1H, dd, J = 6.4 Hz, J = 9.6 Hz), 7.10ꢀ7.31 (15H, m),
8.69ꢀ8.76 (4H, 2d, J = 7.6 Hz). 13C NMR (100 MHz, d6-DMSO):170.1
(C), 169.3 (C), 162.8 (C), 162.1 (C), 144.1 (C), 131.7 (CH), 130.9
(CH), 129.0 (CH) 128.1 (CH), 127.1 (C), 126.9 (CH), 126.7 (C),
126.2 (C), 125.2 (C), 66.5 (C), 55.5 (CH), 52.2 (CH), 32.6 (CH), 30.3
(CH2), 24.6 (CH2), 18.7 (CH3), 11.2 (CH3). Mp: 224 °C dec. HRMS
(ESIþ) (m/z): calcd for C42H36N3O7S [M þ H]þ, 726.2274; found,
726.2285.
162.9 (C), 170.6 (C). Anal. Calcd for C31H27N3O6 H2O: C, 67.02; H,
3
5.26; N, 7.56. Found: C, 66.75; H, 4.89; N, 7.66. Mp: 178 °C.
3j: The reaction was performed on 1.423 mmol (500 mg) of 2b and
1.423 mmol (312 mg) of 4-iodoaniline using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
product as a pale brown solid (300 mg, 38%). 1H NMR (400 MHz, d6-
DMSO): 0.90 (6H, t, J = 7.3 Hz), 1.33 (4H, m), 1.81 (1H, m), 4.03 (2H,
d, J = 7.2 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.93 (2H, d, J = 8.6 Hz), 8.69 (2H,
d, J = 7.6 Hz), 8.70 (2H, d, J = 7.6 Hz). 13C NMR (100 MHz, d6-
DMSO): 10.5 (CH3), 23.0 (CH2), 38.7 (CH), 43.5 (CH2), 123.7 (C),
126.8 (C), 127.0 (C), 128.5 (C), 130.5 (CH), 131.4 (CH), 131.8 (CH),
135.5 (C), 137.9 (CH), 159.7 (C), 162.8 (C), 163.0 (C). Anal. Calcd for
3o: The reaction was performed on 0.163 mmol (100 mg) of 3c and
0.163 mmol (61 mg) of H-L-Cys(Trt)-OMe HCl using general proce-
3
dure B. Yield: 141 mg, 89%. 1H NMR (400 MHz, d-CDCl3): 3.16ꢀ3.25
(4H, m), 3.63(3H, s), 5.47ꢀ5.51 (1H, m), 5.53ꢀ5.57(1H, m),
7.11ꢀ7.34 (30H, m), 8.68ꢀ8.72 (4H, br s). 13C NMR (100 MHz, d-
CDCl3): 172.6 (C), 168.8 (C), 162.3 (C), 162.1 (C), 146.9 (C), 144.4
(C), 144.3 (C), 137.7 (CH), 132.6 (CH), 131.5 (CH), 130.2 (CH),
130.0 (CH), 129.7 (CH), 128.4 (CH), 128.0 (CH), 127.4 (CH), 127.0
(C), 126.9 (C), 126.8 (CH), 126.5 (C), 126.4 (C), 67.6 (C), 67.5 (C),
53.1 (CH), 52.9 (CH), 30.6 (CH2), 30.5 (CH2), 29.8 (CH3). Mp:
174 °C dec. HRMS (ESIþ) (m/z): calcd for C59H44N2O8S2Na [M þ
Na]þ, 995.2431; found, 995.2425.
C26H21IN2O4 H2O: C, 54.75; H, 4.06; N, 4.91. Found: C, 54.76; H,
3
3.86; N, 4.79. Mp: 261 °C dec.
3k: The reaction was performed on 1.423 mmol (500 mg) of 2b and
1.423 mmol (167 mg) of 4-ethynylaniline using general procedure B.
Workup: the brown residue was suspended in acetone and the suspen-
sion added slowly to vigorously stirred 1 M HCl(aq). The precipitate
was filtered and washed with water and dried in vacuo to yield the
product as a pale brown solid (212 mg, 33%). 1H NMR (400 MHz, d6-
DMSO): 0.90 (6H, t, J = 7.3 Hz), 1.35 (4H, m), 1.82 (1H, m), 4.03 (2H,
d, J = 7.2 Hz), 4.31 (1H, s), 7.76 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4
Hz), 8.69 (2H, d, J = 7.8 Hz), 8.70 (2H, d, J = 7.8 Hz). 13C NMR (100
MHz, d6-DMSO):10.5 (CH3), 23.0 (CH2), 38.7 (CH), 43.4 (CH2),
81.6 (C), 82.9 (CH), 122.0 (C), 126.26 (C), 126.34 (C), 126.6 (C),
126.8 (C), 129.5 (CH), 130.4 (CH), 130.6 (CH), 132.4 (CH), 136.1
3p: The reaction was performed on 0.163 mmol (100 mg) of 3c and
0.163 mmol (59 mg) of H-L-Cys(Trt)-NH2 using general procedure B.
Yield: 133 mg, 85%. 1H NMR (400 MHz, d6-DMSO): 2.86ꢀ2.97 (2H,
m), 3.09ꢀ3.13 (1H, dd, J = 3.2 Hz, J = 10.4 Hz), 3.17ꢀ3.21 (1H, dd, J =
4.0 Hz, J = 10.4 Hz), 5.37ꢀ5.40 (1H, dd, J = 3.2 Hz, J = 8.4 Hz),
5.56ꢀ5.89 (1H, dd, J = 3.6 Hz, J = 8.0 Hz), 7.14ꢀ7.22 (30H, m),
8.70ꢀ8.755 (4H, 2d, J = 6.4 Hz). 13C NMR (100 MHz, d6-DMSO):
169.2 (C), 168.9 (C), 162.3 (C), 161.9 (C), 144.2 (C), 144.0 (C), 131.5
(CH), 130.9 (CH), 128.9 (CH), 128.0 (CH), 127.9 (CH), 126.9 (CH),
126.8 (CH), 126.7 (CH), 126.5 (CH), 126.1 (C), 125.3 (C), 66.4 (C),
66.3 (C), 53.0 (CH), 52.2 (CH), 30.3 (CH2), 30.1 (CH2). Mp: 198 °C
dec. HRMS (ESIþ) (m/z): calcd for C58H43N3O7S2Na [M þ Na]þ,
980.2420; found, 980.2424.
(C), 162.8 (C), 163 (C). Anal. Calcd for 2C28H22N2O4 H2O: C, 73.19;
3
H, 5.05; N, 6.10. Found: C, 73.30; H, 4.92; N, 6.06. Mp: 284 °C dec.
3l: The reaction was performed on 0.163 mmol (100 mg) of 3c and
0.163 mmol (22 μL) of 2-ethylbuytlamine using general procedure B.
Yield: 93 mg, 94%. 1H NMR (400 MHz, d-CDCl3): 0.96ꢀ0.99 (6H, t,
J = 6.4 Hz), 1.35ꢀ1.44 (4H, dt, J = 6.8 Hz, J = 12.8 Hz), 1.85ꢀ1.92 (1H,
m), 3.14ꢀ3.25 (2H, m), 4.14ꢀ4.16 (2H, d, J = 7.2 Hz), 5.53ꢀ5.57 (1H,
dd, J = 5.2 Hz, J = 9.6 Hz), 7.11ꢀ7.32 (15H, m), 8.70ꢀ8.76 (2H, 2d, J =
8.1 Hz). 13C NMR (100 MHz, d-CHCl3): 172.7 (C), 163.3 (C), 162.2
(C), 144.4 (C), 131.7 (CH), 131.2 (CH), 129.7 (CH), 128.1 (CH),
127.1 (C), 126.9 (CH), 126.2 (C), 67.6 (C), 53.0 (CH), 44.6 (CH2),
39.7 (CH), 30.6 (CH2), 23.7 (CH2), 10.8 (CH3). Mp: 120 °C dec.
HRMS (ESIþ) (m/z): calcd for C42H36N2O6SNa [M þ Na]þ,
719.2186; found, 719.2176.
3q: The reaction was performed on 0.163 mmol (100 mg) of 3c and
0.163 mmol (40 mg) of H-L-Lys(Boc)-OH using general procedure B.
1
Yield: 137 mg, 87%. H NMR (400 MHz, d-CDCl3): 1.27 (9H, s),
1.50ꢀ1.33 (2H, m), 2.21 (2H, m), 2.58 (2H, m), 3.11 (2H, m), 3.30
(2H, m), 5.46 (1H, d, J = 6.1 Hz), 5.54 (1H, m), 7.0ꢀ7.21 (15H, m),
8.61ꢀ8.76 (4H, 2d, J = 7.6 Hz). 13C NMR (100 MHz, d-CDCl3):173.1
(C), 171.7 (C), 162.7 (C), 162.3 (C), 144.5 (C), 131.5 (CH), 129.7
(CH), 128.0 (CH), 126.8 (CH), 126.6 (C), 67.6 (C), 53.8 (CH), 53.2
(CH), 36.9 (CH2), 31.7 (CH2), 30.7 (CH2), 29.8 (CH2), 28.5 (CH3),
23.9 (CH2). Mp: 230 °C dec. HRMS (ESIþ) (m/z): calcd for
C47H43N3O10SNa [M þ Na]þ (m/z) 864.2567; found, 864.2564.
3r: The reaction was performed on 0.163 mmol (100 mg) of 3e and
0.163 mmol (21 mg) of H-L-Gly-OMe HCl using general procedure B.
3
3m: The reaction was performed on 0.163 mmol (100 mg) of 3c and
0.163 mmol (39 mg) of H-L-Phe(4-Br)-OH using general procedure B.
Yield: 123 mg, 90%. 1H NMR (400 MHz, d6-DMSO): 2.89ꢀ2.95 (1H,
dd, J = 10.8 Hz, J = 13.2 Hz), 3.11ꢀ3.16 (1H, dd, J = 4.8 Hz, J = 13.2 Hz),
3.27ꢀ3.32 (1H, dd, J = 6.4 Hz, J = 11.2 Hz), 3.56ꢀ3.61 (1H, dd, J = 5.6
Hz, J = 14.0 Hz), 5.51ꢀ5.55 (1H, dd, J = 4.4 Hz, J = 10.4 Hz), 5.85ꢀ5.88
Yield: 105 mg, 94%. 1H NMR (400 MHz, d6-acetone): 3.14ꢀ3.17 (1H, dd,
J=5.2Hz, J= 11.2 Hz), 3.40ꢀ3.44 (1H, dd, J=5.2Hz, J=12Hz), 3.78(3H,
s), 4.94(2H, s), 5.60ꢀ5.64 (1H, dd, J = 3.6 Hz, J = 10.4 Hz), 7.17ꢀ7.33
(15H, m), 8.78ꢀ8.85 (4H, 2d, J = 7.6 Hz). 13C NMR (100 MHz, d6-
acetone): 169.2 (C), 168.4 (C), 162.7 (C), 145.0 (C), 133.5 (CH), 132.2
(CH), 130.9 (CH), 128.9 (CH), 127.7 (C), 67.1 (C), 54.6 (CH), 53.1
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ARTICLE
(CH2), 42.6 (CH3), 31.5 (CH2). Mp: 168 °C dec. HRMS (ESIþ) (m/z):
calcd for C39H29N3O7SNa [M þ Na]þ, 706.1624; found, 706.1611.
3s: The reaction was performed on 0.160 mmol (100 mg) of 3b and
Author Contributions
These authors contributed equally.
0.160 mmol (20 mg) of H-L-Gly-OMe HCl using general procedure B.
3
Yield: 99 mg, 90%. 1H NMR (400 MHz, d-CDCl3): 2.94ꢀ3.00 (1H, dd,
J = 6.4 Hz, J = 14.2 Hz), 3.61ꢀ3.67 (1H, dd, J = 8.4 Hz, J = 14.2 Hz), 3.81
(3H, s), 4.98 (2H, s), 6.22ꢀ6.26 (1H, t, J = 8 Hz), 6.90 (1H, s)
7.11ꢀ7.16 (15H, m), 8.70ꢀ8.77 (4H, 2d, J = 7.6 Hz). 13C NMR (100
MHz, d-CDCl3): 171.4 (C), 168.9 (C), 168.0 (C), 162.3 (C), 162.2 (C),
144.0 (C), 131.4 (CH), 131.3 (CH), 128.5 (CH), 127.8 (CH), 127.0
(CH), 126.9 (C), 126.8 (C), 126.4 (C), 126.3 (C), 70.9 (C), 52.7 (CH3),
50.2 (CH), 41.5 (CH2), 37.4 (CH2). Mp: 174 °C dec. HRMS (ESIþ) (m/
z): calcd for C40H30N3O9 [M þ H]þ, 696.1982; found, 696.1974.
3t: The reaction was performed on 0.187 mmol (100 mg) of 3n and
0.187 mmol (25 μL) of 2-ethylbutylamine using general procedure B.
Yield: 106 mg, 91%. 1H NMR (400 MHz, d-CDCl3): 0.85ꢀ0.89 (6H, t,
J = 7.6 Hz), 1.26ꢀ1.37 (4H, m), 1.76ꢀ1.83 (1H, m), 3.35ꢀ3.41 (1H,
dd, J = 10 Hz, J = 14.2 Hz), 3.56ꢀ3.61 (1H, dd, J = 5.6 Hz, J = 14.2 Hz),
3.701 (3H, s), 4.06ꢀ4.08 (2H, d, J = 7.2 Hz), 4.82 (2H, s), 5.89ꢀ5.93
(1H, dd, J = 5.6 Hz, J = 10 Hz), 6.63ꢀ6.65 (2H, d, J = 8.4 Hz), 6.98ꢀ7.00
(2H, d, J = 8.8 Hz), 7.19ꢀ7.23 (5H, m), 8.58ꢀ8.66 (4H, 2d, J = 7.6 Hz).
13C NMR (100 MHz, d-CDCl3): 170.1 (C), 163.5 (C), 162.8 (C), 157.9
(C), 137.2 (C), 131.7 (CH), 131.4 (CH), 130.5 (CH), 129.4 (C), 128.9
(CH), 128.3 (CH), 127.7 (CH), 127.3 (C), 127.2 (C), 126.3 (C), 115.2
(CH), 70.2 (CH2), 55.2 (CH), 53.1 (CH3), 44.7 (CH2), 39.7 (CH),
34.3 (CH2), 23.9 (CH2), 11.0 (CH3). Mp: 86 °C dec. HRMS (ESIþ)
(m/z): calcd for C37H35N2O7 [M þ H]þ, 619.2444; found, 619.2442.
3u: The reaction was performed on 0.187 mmol (100 mg) of 3n and
’ ACKNOWLEDGMENT
We thank Prof. Jeremy K. M. Sanders for his support and
helpful suggestions and Mr. Matej Janecek and Miss Elizabeth
Howe for their contribution in the early stages of this work. We
thank the Chemistry Department, University of Cambridge (K.
T.), the Gates Cambridge Trust (N.P.), The Royal Society, Grant
IJP 2008/R2 (G.H. and G.D.P.), Pembroke College, Cambridge,
and the University of Bath (G.D.P.) for funding.
’ REFERENCES
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S. A.; Tseng, H. -R.; Jarrosson, T.; Sanders, J. K. M.; Marchioni, F.;
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0.187 mmol (23 mg) of H-L-Gly-OMe HCl using general procedure B.
3
Yield: 105 mg, 93%. 1H NMR (400 MHz, d-CDCl3): 3.35ꢀ3.41 (1H,
dd, J = 10 Hz, J = 14.2 Hz), 3.56ꢀ3.61 (1H, dd, J = 5.6 Hz, J = 14.2 Hz),
3.70 (3H, s), 3.73 (3H, s), 4.82 (2H, s), 4.89 (2H, s), 5.89ꢀ5.93 (1H, dd,
J = 5.6 Hz, J = 10 Hz), 6.63ꢀ6.65 (2H, d, J = 8.4 Hz), 6.98ꢀ7.00 (2H, d,
J = 8.8 Hz), 7.19ꢀ7.23 (5H, m), 8.60ꢀ8.68 (4H, 2d, J = 7.6 Hz). 13C
NMR (100 MHz, d-CDCl3): 170.1 (C), 168.4 (C), 162.8 (C), 162.6
(C), 137.2 (C), 131.7 (CH), 130.5 (CH), 129.4 (C), 128.8 (CH), 128.3
(CH), 127.7 (CH), 127.3 (C), 127.2 (C), 126.7 (C), 115.2 (CH), 70.2
(CH2), 55.3 (CH), 53.1 (CH3), 41.9 (CH2), 34.3 (CH2). Mp: 84 °C
dec. HRMS (ESIþ) (m/z): calcd for C34H27N2O9 [M þ H]þ,
607.1717; found, 607.1724.
(3) (a) Mareda, J.; Matile, S. Chem.—Eur. J. 2009, 15, 28–37. (b)
Dawson, R. E.; Hennig, A.; Weimann, D. P.; Emery, D.; Ravikumar, V.;
Montenegro, J.; Takeuchi, T.; Gabutti, S.; Mayor, M.; Mareda, J.;
Schalley, C.; Matile, S. Nat. Chem. 2010, 2, 533–538.
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I. W.; Rowan, S. J. J. Am. Chem. Soc. 2010, 132, 12051–12058. (f) Iengo,
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Moiseev, A. G.; Perepichka, D. F. J. Mater. Chem. 2011, 21, 1470–1478.
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3v: The reaction was performed on 0.187 mmol (100 mg) of 3n and
0.187 mmol (48 mg) of H-L-Phe-OtBu HCl using general procedure B.
3
1
Yield: 116 mg, 84%. H NMR (400 MHz, d-CDCl3): 1.46 (9H, s),
3.39ꢀ3.47 (2H, m), 3.62ꢀ3.69 (2H, m), 3.76 (3H, s), 4.90 (2H, s),
5.91ꢀ5.99 (2H, m), 6.71ꢀ6.74 (2H, d, J = 8.4 Hz), 7.05ꢀ7.16 (8H, m),
7.27ꢀ7.31 (4H, m), 8.64 (4H, s). 13C NMR (100 MHz, d-CDCl3):
170.3 (C), 162.7 (C), 137.6 (C), 137.2 (C), 131.7 (CH), 130.5 (CH),
129.4 (CH), 128.8 (CH), 128.3 (CH), 127.8 (CH), 127.1 (CH), 126.7
(C), 126.4 (C), 119.9 (C), 115.2 (CH), 82.8 (C), 70.4 (CH2), 56.4
(CH), 55.3 (CH), 53.1 (CH3), 35.8 (CH2), 34.2 (CH2), 28.6 (CH3).
Mp: 112 °C dec. HRMS (ESIþ) (m/z): calcd for C44H38N2O9Na [M þ
Na]þ, 761.2475; found, 761.2468.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C spectra and char-
S
b
acterization details for all compounds, synthetic procedures,
X-ray diffraction data, and CIF data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7) (a) Panto-s, G. D.; Pengo, P.; Sanders, J. K. M. Angew. Chem., Int.
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G. D.; Sanders, J. K. M. Chem.—Eur. J. 2010, 16, 81–84. (d) Tamanini,
E.; Ponnuswamy, N.; Panto-s, G. D.; Sanders, J. K. M. Faraday Discuss.
2010, 145, 205–218.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: g.d.pantos@bath.ac.uk.
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ARTICLE
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